Pharmaceutical parenteral admixtures are a combination of sterile drugs that are mixed together under aseptic conditions and are intended for intravenous infusion. These admixtures may be relatively simple or extremely complex, with the complexity increasing with the inclusion of multiple active ingredients. Nutrition admixtures are one example of complex parenteral admixtures that are frequently prepared in a hospital pharmacy for treating patients in the hospital. In general parenteral nutrition admixtures (“PN”) refer to most types of nutritional solutions for intravenous feeding. Total patenteral nutrition admixtures (“TPN”) generally refer to those PNs that do not contain lipids as a component, and total nutritional admixtures (“TNA”) refer to those PN's that contain lipids.
The pharmacy of a hospital, a compounding center or a care facility prepares or compounds a prescription which typically has been determined by a physician singularly or in conjunction with a dietician, pharmacist or other care provider. The pharmacy may be required to compound large numbers of PN on a daily basis. The actual PN compounding is done primarily by electomechanical mixing equipment called compounders which are extremely sophisticated and are adapted to admix many different components in differing proportions as set forth in pharmaceutical prescriptions.
Compounders include high volume compounders which are adapted to prepare PN by transferring those components which are normally found in relatively large volumes in a PN, for example amino acids, sterile water, lipids and dextrose, at a relatively high speed. Such compounders include the AUTOMIX 3+3 compounder manufactured by the Clintec Nutrition Division of Baxter Healthcare Corporation.
Compounders also include low volume compounders such as compounders from the same corporation marketed as a MICROMIX compounder. The MICROMIX compounder is adapted to accurately transfer those components that are normally found in relatively small volumes in a PN.
It is common for pharmacies to produce a prescribed PN by utilizing both a MICROMIX and an AUTOMIX compounder, typically by adding the high volume components to the final container or final bag with the AUTOMIX compounder and then transferring the final bag to the MICROMIX compounder for transferring the smaller volume components. It should be understood that a single compounder may have the capability of transferring both high volume components and low volume components either sequentially or concurrently. Alternatively, the single compounder could have both a high volume module and a low volume module that could transfer fluid to a common manifold, a common transfer tube connected to a final bag or container, or into separate ports in a final bag.
To prepare such PN at an acceptable cost it is important that the PN are compounded as efficiently as possible. Efficiency is generally achieved by seeking to maximize the number of PN's prepared over a given period of time or “throughput”. However, the complexity of properly preparing PN tends to slow down such throughput. Areas of complexity may be found in determining the proper PN for a given prescription for a particular patient, accurately preparing the PN and accounting or billing for the PN. However, safety of the patient is paramount and efficient PN preparation must be accomplished with little possibility of errors.
In preparing the proper prescription for a particular patient the pharmacist must perform many tasks including evaluation and determination of the proper components and their respective amounts. Patient specific factors including the type of patient i.e. neonatal, and weight of patient, will be considered. Improving the ability of the pharmacist in making such evaluations and determinations will increase the throughput and reduce the possibility of errors. For record keeping purposes it is desirable and on occasion required for the pharmacist to note in a permanent record why the prescription differs from generally desired amounts of source solutions.
As is well known in pharmacy practice, much of the complexity involved in preparing PN results from compatibility issues relating to the components that are placed in the prescribed PN. Compatibility is defined as the interaction between a drug and all other components with which that drug comes into contact, including but not limited to the diluent, the container and other drugs in the same PN. Compatibility is divided into two subcategories which are physical as well as chemical compatibility. Physical compatibility is defined as an incompatibility that will alter the physical appearance of the drug, typically resulting in a visual change such as precipitation, gas evolution or a change in color. Chemical incompatibilities are not visually observed but must be analytically tested. Chemical incompatibilities occur as a result of changes in the active drug such as oxidation or photodegradation. Factors that can influence compatibility include, but are not limited to the total diluent volume, concentration levels, the order of admixing and the pH.
There are two steps in the evaluation of compatibility and parenteral admixtures. First, compatibility of the entire PN over the period between preparation of the admixture and completion of delivery to the patient should be evaluated prior to compounding. Secondly, the compounding preparation process must be planned in a way to allow for compatibility while the compounding process is proceeding. For example, the compatibility between a source solution being added to the final mixing container or any intermediate mixing container and the solution present in that container should be evaluated. In many instances source solutions which are packaged at concentrations which are incompatible with other solutions must be diluted before they come into contact with each other in such chambers.
As can be appreciated the highest dilution will occur when the greatest amount of diluting fluids are already present in the container into which the solutions are being added. For example, amino acid or dextrose source solutions will form a large portion of a PN and yet are typically compatible with most additives. Thus it would seem to that these solutions would be transferred first to the final container or to any intermediate mixing chambers to dilute added source solutions.
An additional complexity that must be considered is the prevention of the contact between highly concentrated solutions which are incompatible with each other along a common flowpath in the compounder. In a representative instances, although source solutions may flow along separate tubes for much of a transfer flowpath, there may be a section along a transfer flowpath which is common to the two incompatible source solutions. This common flow path may be found along any part of the flow path such as in an intermediate mixing chamber or after the intermediate mixing chamber or after a switching valve.
One method to reduce the possibility of a solution being incompatible with a second solution along a common flow path is to flush the common flow path after each solution has been transferred. Such flushing is accomplished with a solution which is compatible with both the prior solution as well as the solution to be added after the flush. As can be appreciated frequent flushing dilute the incompatible solutions thereby making them compatible but will also decrease throughput.
Also there must be a source of fluid for such a flushing scheme. The source of such flushing solutions may either be a compatible source solution which forms a part of the prescription or the solution present in a downstream chamber such as an admixture in the final mixing container. However, in present pharmacy practices, the prescribed amount of solutions which are used as flushing solutions are typically transferred first to the final container for expediency and dilution purposes and are not available as flushing solutions. In this instance and by default the solution in the final bag must be compatible with the solution which is to be flushed, and the flushing solution will be drawn from the final container. Drawing the flush from the final bag and returning the flush to the final bag decreases throughput. On the other hand holding back an amount of the diluting source solutions for flushing may lead to instances where two incompatible solutions come into contact with each other in the final mixing chamber without being properly diluted to a compatible concentration.
In an effort to increase efficiency, a pharmacist will typically group solution containers in dependence on the operating scheme of the compounder so that ingredients which are compatible with each other (at source solution concentration) are added together sequentially between rinses which are set by the pharmacist. After making a determination regarding the compatibility of the various solutions the pharmacist may group a set of compatible solutions on station 1-4, a second set of compatible of compatible solutions on stations 5-8, etc with rinses set after station 4, station 8, etc. However, a particular admixture may require 5 solutions which are compatible. Because setting rinses requires greater time and effort, the pharmacist may hang the fifth ingredient at a station which has rinses before and after rather than adjust the station arrangement and rinsing scheme. This however is not optimal.
Another consideration for a pharmacist when compounding multiple prescriptions comprising a mixture of TNA and TPN is lipid hazing in which a trace of lipid is present in a final solution which is not to contain lipids. Hazing can be produced by lipids being present in amounts as low as one to 3 parts per million. Such hazing will typically occur when a prescription containing lipids is compounded immediately prior to a prescription which is not to contain lipids. Lipid hazing is not generally believed to create a health hazard, however lipid hazing in a PN which is to be infused may be later mistaken for a PN with unacceptable precipitation arising from an error in formulating a compatible PN solution, and the hazy solution may be mistakenly discarded.
If lipid hazing is an issue the pharmacist may seek to avoid such problems by flushing the compounder after each prescription containing lipids is compounded. However, such flushing will decrease throughput and not be totally effective. To increase throughput, the pharmacist may decrease such flushing by grouping lipid prescriptions; however such groupings have a negative impact on flexibility. If lipid hazing is not an issue, the possibility of lipid hazing should be communicated to persons who are compounding the solution and who are administrating the PN to the patient to prevent the administer from mistakenly believing that the admixture has become unstable.
Other methods of seeking to prevent lipid hazing are to use a completely separate flowpath for the lipids to the final mixing container. However, once lipids are present in a final container flushing or rinsing using solution from the final container will introduce lipids into the flowpath and may cause lipid hazing in a subsequent PN.
Adding to the complexity of compounding the pharmacist must consider is the accuracy limits of the compounders such that prescriptions which have ingredients in volume levels below the accuracy limit of the compounder will likely be added by hand utilizing a syringe. Such manual addition decreases throughput. Also inefficiencies inherent in the administration of the PN to the patient such as residual volumes in administration sets must also be considered. Accounting for the complexities has proven to be time consuming and lead to inefficient activities and practices.
For reimbursement and record keeping purposes, the prepared admixture must be accounted for which is generally accomplished by reporting either manually or electronically transferring information into a facility's accounting system. The steps the pharmacist must perform to insure that an admixture is properly accounted for should be minimized to increase efficiency.